Though transmission of indigenous African monkey lentiviruses to humans or to Asian macaques has resulted pathogenic consequences for the new host, it is becoming increasingly clear that pathogenic cross- species lentiviral infection is an exceptional occurrence. Recent studies indicate innate cellular restriction factors are key to limiting such infections, and that lentiviral adaptation to a new host requires alterations in accessory gene structure, i.e., viral infectivity factor (Vif). To study this issue, we developed a feline model of cross-species lentiviral transmission that results in productive, yet regressive, avirulent infection, and have determined that such infection attenuates subsequent virulent feline immunodeficiency virus (FIV) challenge. Data published during the initial grant cycle demonstrate that innate cellular responses, namely cytokine expression profiles and cytidine deaminase-like (CD) activity resulting in high viral error burden, are more significant for host viral control than adaptive immune responses-which follow rather than precede viral down regulation. Moreover, virulent FIV-C-PG disease attenuation (i.e. protection from CD4+ T cell depletion and modulation of viral set point) in cats infected with avirulent puma lentivirus (PLV-1695), is associated with unique FIV molecular evolution, and maintenance of a proinflammatory cytokine profile vs. cats infected with virulent FIV-C-PG alone-and disease modulation occurs despite disparities in receptor use and target cell distribution between FIV and PLV. Here we propose to advance this unique feline model to address important questions in lentivirus biology: (a) How does host innate activity (defined by CD-like hypermutation and cytokine cell-signaling) relate to attenuation of disease? and (b) What role does Vif play in modulating virulent lentiviral challenge? To answer these questions, we propose: (1) To determine whether previous PLV-1695 infection enhances hypermutation, error burden, and tissue-specific cytidine deaminase activity/cytokine expression after FIV-C-PG challenge;and, (2) To determine whether Vif modulates CD activity and cytokine activation as a mechanism of attenuation. These experiments pose a new paradigm for assessment of protective immunity against HIV/AIDS-namely, that enhancement of early innate immune parameters by exposure to an avirulent, non-adapted lentivirus can provide cross-protective activity against a virulent, host-adapted lentivirus, and as such, these studies are of great public health significance.